Abstract

Introduction: The Abscopal effect refers to radiotherapy-induced tumor regression in lesions distant from a targeted site, and is a rare phenomenon in patients receiving local radiotherapy. This report is the first to describe an Abscopal response in a chemotherapy-naïve non-small cell lung cancer (NSCLC) patient following whole-brain radiotherapy as well as palliative radiotherapy.

Case presentation: A 63-years-old man who was a current-smoker (with 86 pack years) with metastatic NSCLC underwent whole brain radiotherapy (WBRT) plus boost radiotherapy to total dose of 45 Gy in 15 fractions because the metastatic brain tumor with cerebral oedema from the left temporal lobe to the occipital lobe rapidly progressed after the enucleation of the brain tumor. The patient also received palliative radiation (30 Gy in 10 fractions) for the third lumbar vertebral metastasis. The tumor in the left upper lobe of the lung and his mediastinal lymph nodes had regressed in size upon reviewing his follow-up CT results seven weeks post-radiotherapy.

Conclusion: The Abscopal effect in metastatic NSCLC patients can occur after the irradiation of metastatic lesions without chemotherapeutic or immunotherapeutic interventions.

Keywords

Non-small cell lung cancer; Abscopal response;
Radiotherapy

Introduction

The Abscopal effect refers to radiation-induced tumor regression
in lesions that are distant from a targeted site, and has been recognized
for six decades as a rare, unexplained phenomenon in patients receiving
local radiotherapy [1]. According to our knowledge, the radiation
therapy is not available in patients with multiple metastatic cancer.
The abscopal effect is observed outside the treated field of radiation,
but it is underrecognized in the clinical practice [2,3]. Recent studies
have suggested that the Abscopal effect may result from radiotherapyinduced
immune system-mediated cancer cell death [4-6]. In support
of this hypothesis, the Abscopal effect was reported in a patient who
was treated with ipilimumab and fractionated radiotherapy [7].
However, the possibility that ipilimumab alone might be responsible
for the patient’s response cannot be ruled out, because some non-small
cell lung cancer (NSCLC) patients receiving immunotherapeutic agents
such as nivolumab achieved good responses and longer progressionfree
survival rates [8,9].

We encountered a patient with metastatic NSCLC who experienced
the Abscopal effect after whole-brain radiotherapy (WBRT) and
palliative radiation for vertebral metastasis in a patient.

Case Presentation

A 63-year-old man who was a current smoker (40 cigarettes a
day for 43 years) presented with worsening dysgraphia and memory
impairment. Chest radiography and computed tomography (CT)
revealed a 4 cm solitary tumor in the upper lobe of the left lung with
mediastinal lymphadenopathy, and magnetic resonance imaging (MRI)
revealed a 3 cm solitary tumor, assumed to be a metastatic lesion,
with cerebral edema extending from the left temporal lobe to the
occipital lobe. Bronchoscopic cytology from the lung tumor revealed
malignant cells that were consistent with NSCLC. Bone scintigraphy
with 99mTc-methylene diphosphonate demonstrated intense uptake in the third lumbar vertebra. The patient was thus diagnosed with NSCLC,
cT2aN2M1b, stage IV. Because his symptoms progressed rapidly,
he underwent enucleation of the brain tumor as initial treatment.
Pathological examination of the excised cranial lesion confirmed it
to be an NSCLC metastasis. Immunohistochemistry revealed positive
expression of TTF-1 and CK7, whereas CK20, CA19-9, and CDX-
2 were negative. Tumor-infiltrating lymphocytes were not observed
extensively; however, the brain metastasis progressed immediately after
the surgery, and WBRT was therefore performed with a total of 45 Gy
in 15 fractions (30 Gy/10 fractions as WBRT, and 15 Gy/5 fractions as
boost-radiotherapy). The patient also received palliative radiation (30
Gy in 10 fractions) for the third lumbar vertebral metastasis (Figure 1).

The patient’s lung tumor immediately shrank after radiotherapy as
observed by radiography. The tumor in the left upper lobe of the lung
had regressed in size upon reviewing his follow-up CT results seven
weeks post-radiotherapy (43 mm to 26 mm: 40% reduction), as had his
mediastinal lymph nodes (Figure 2). After we confirmed the Abscopal
effect, the patient received four cycles of cisplatin, gemcitabine, and
bevacizumab, and was maintaining a good clinical response at his
9-month follow-up session. At this time, disease progression was
observed with an increase in the primary tumor size and multiple
pulmonary metastases.

Discussion

To our knowledge, ours is the first patient with metastatic NSCLC
who was reported to exhibit the Abscopal effect after WBRT and
palliative radiation without having undergone chemotherapy or
immunotherapy.

There are few reports of the Abscopal effect in patients with
NSCLC; however, those that involved patients who were treated with
radiotherapy alone exhibited reduced metastatic sites after primary site
irradiation [10-12]. Our case was distinct in that the Abscopal effect
was observed in primary lung tumors directly following the irradiation
of metastatic sites, in the absence of intervening immunotherapy.

The cytotoxic effects of radiotherapy have been attributed to
double-stranded DNA damage. However, recent studies suggest that
the immunomodulatory effects of radiotherapy can contribute to its
therapeutic efficacy. Some preclinical experiments have shown that
radiotherapy inhibits the mechanisms of tumor immune escape by
destroying tumor cells and releasing tumor-associated antigens. These
antigens in turn bind antigen presenting cells that then activate tumorspecific
cytotoxic T cells. The antitumor activity of cytotoxic T cells can
be observed in the non-irradiated field. Such Abscopal responses can
be achieved by irradiating either primary or metastatic tumors [13-18].

Recently, the Abscopal effect was observed after the initiation of
treatment with ipilimumab and fractionated radiotherapy in a patient
with chemotherapy-refractory metastatic adenocarcinoma of the lung
[7]. As previously mentioned, the Abscopal response has been observed
following radiotherapy alone. However, the antitumor function is
suppressed by regulatory T cells and immune checkpoint proteins such
as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed
cell death protein 1 (PD-1), and its ligand PD-L1. Immune checkpoint
inhibitors can strengthen the antitumor immune function caused by
radiotherapy, especially as the latter increases the expression of PD-L1
on tumor cells [19]. In fact, combined blockade of PD-1 and CTLA-
4 during radiotherapy demonstrated a significant therapeutic effect
in both irradiated and non-irradiated large-burden tumors in vivo
[20]. However, the possibility that ipilimumab alone might have been
responsible for the aforementioned patient’s response cannot be ruled
out. In contrast, our case showed the occurrence of the Abscopal effect
after the irradiation of metastatic lesions without having administered
chemo- or immunotherapeutic agents such as ipilimumab. Although
our case is rare, it supports the notion that radiotherapy alone can
indeed induce the regression of non-irradiated tumors.

A combination of local radiotherapy and immunotherapy might
be more effective than immunotherapy alone to improve the outcomes
of select patients with metastatic NSCLC, and our patient may serve
as a study-worthy example of the Abscopal effect occurring after
radiotherapy. Further studies are warranted to clarify the relationship
between the Abscopal effect and immunotherapy/radiotherapy in
order to better identify patients with NSCLC who will benefit from
combination therapy.

Conclusion

The Abscopal effect in metastatic NSCLC patients can occur after
the irradiation of metastatic lesions without chemotherapeutic or
immunotherapeutic interventions.